Resolution of neutrophil response for effective T cell functions and tissue repair

项目摘要/摘要--项目1 中性粒细胞向组织感染部位的迁移对于病原体清除和宿主存活至关重要。 重要的是，一旦他们完成了他们的行动，在感染早期渗透的中性粒细胞应该 迅速启动自发性细胞凋亡。中性粒细胞延迟分解通常与广泛的 严重感染患者的组织损伤、器官衰竭和最终死亡。因此，出现了 长期以来，感染过程中未溶解的中性粒细胞反应一直被认为是有害的，使其更容易 患者难以康复。尽管现在越来越多的证据表明，中性粒细胞不仅有助于 组织损伤，还协调T细胞功能和组织修复，这一直是一个挑战 区分中性粒细胞的宿主保护作用和它们的破坏性炎症功能，因为大多数 这些研究使用了过度激活或不适当的炎症反应，这些反应无法恢复组织 动态平衡。因此，中性粒细胞对宿主免疫反应和组织修复的贡献可能不会 在这些模型中得到适当的评估。我们进行了这项研究，以解决以下关键知识差距 中性粒细胞在感染过程中的功能和去向。通过我们初步调查中的几条证据 使用完全恢复的小鼠流感感染模型进行研究，我们提出了中性粒细胞的新功能，即 能积极促进组织愈合和消退炎症。我们发现，细胞凋亡 中性粒细胞积极参与周围其他细胞(如上皮细胞)的增殖和存活 和巨噬细胞)。中性粒细胞的这种促有丝分裂和促存活作用主要是通过 分泌表皮生长因子(EGF)。此外，我们的活体多光子显微镜(IV-MPM) 新生的Ly6GCre/ROSAtdTomato/CSF1R-EGFP小鼠显示出显著的中性粒细胞运动模式和 它们在受感染的呼吸道内的溶解阶段的吞噬细胞，这可能代表着 中性粒细胞在保护宿主免受感染方面的有益功能。我们假设解决方案是 流感感染期间的中性粒细胞反应不仅仅是早期中性粒细胞的被动终止 渗透而不是活跃的生化和细胞过程，以建立有效的T细胞免疫反应 同时使组织能够修复并恢复正常功能。我们将检验以下假设：(1)细胞凋亡 中性粒细胞促进组织修复，(2)中性粒细胞控制自己的清除。我们还将确定(3) 中性粒细胞分解是否调节T细胞功能和记忆形成。考虑到重要的免疫力- 中性粒细胞的调节特性，了解中性粒细胞在分解过程中的新功能 炎症可以被用来对抗感染和慢性炎症。

PROJECT SUMMARY/ABSTRACT – PROJECT 1 Migration of neutrophils to sites of tissue infection is vital for pathogen clearance and, thus, host survival. Importantly, once they complete their action, infiltrated neutrophils during the early infection phase should quickly initiate spontaneous apoptosis. A delayed neutrophil resolution is often associated with widespread tissue damage, organ failure, and ultimately death in severely infected patients. Therefore, the presence of unresolved neutrophil response during infection has long been believed to be detrimental, making it more difficult for patients to recover. Although growing evidence now suggests that neutrophils not only contribute to the tissue damage, but also orchestrate T cell functions and tissue repair, it has been challenging to clearly differentiate host-protective roles of neutrophils from their damaging inflammatory functions because most of the studies used over-activated or inappropriate inflammatory responses, which fail to restore tissue homeostasis. Therefore, the contribution of neutrophils to the host immune response and tissue repair may not be properly evaluated in these models. We undertook this study to address critical knowledge gaps regarding the function and fate of neutrophils during the infection. Through several lines of evidence from our preliminary study using a fully recovering mouse influenza infection model, we propose novel functions of neutrophil that can actively promote tissue healing and the resolution of inflammation. We discovered that apoptotic neutrophils actively engage with the proliferation and survival of other surrounding cells (e.g., epithelial cells and macrophages). This mitogenic and pro-survival effect of apoptotic neutrophils was mainly mediated by the secretion of epidermal growth factor (EGF). Moreover, live intravital multiphoton microscopy (IV-MPM) of our newly generated Ly6GCre/ROSAtdTomato/Csf1r-EGFP mice revealed a striking motility pattern of neutrophils and their phagocytes during the resolution phase within the infected airway, which may represent additional beneficial functions of neutrophils in protecting the host against infections. We hypothesize that resolution of neutrophil response during influenza infection is not merely a passive termination of the early neutrophil infiltrates but rather an active biochemical and cellular process to establish effective T cell immune responses while enabling tissues to repair and return to normal function. We will test the hypothesis that (1) apoptotic neutrophils promote tissue repair and (2) neutrophils control their own clearance. We will also determine (3) whether neutrophil resolution regulates T cell functions and memory formation. Given the important immune- modulatory properties of neutrophils, understanding of novel functions of neutrophil during the resolution of inflammation could be harnessed to combat infection and chronic inflammatory conditions.